Heat-shock chaperone HSPB1 regulates cytoplasmic TDP-43 phase separation and liquid-to-gel transition.
Heat-shock chaperone HSPB1 regulates cytoplasmic TDP-43 phase separation and liquid-to-gel transition.
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DOI：
10.1038/s41556-022-00988-8
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发表时间：
2022-09
影响因子：
21.3
通讯作者：
中科院分区：
文献类型：
--
作者：
虽然乙酰化的RNA结合缺陷型TDP-43在细胞核内可逆地相分离成由含TDP-43的液体外壳和HSP 70家族分子伴侣的液体中心组成的复杂液滴（异质体），但TDP-43的细胞质聚集体是多种神经退行性疾病（包括ALS）的标志。在这里，我们表明，短暂的氧化应激，蛋白酶体抑制，或抑制HSP 70的ATP依赖的伴侣活性引起可逆的细胞质TDP-43的去混合和从液体到凝胶/固体的过渡，独立于RNA结合或应力颗粒。同位素标记质谱用于鉴定相分离的细胞质TDP-43被小的热休克蛋白HSPB 1结合。结合是直接的，通过TDP-43的RNA结合和低复杂性结构域介导。HSPB 1分配到TDP-43液滴中，抑制TDP-43组装成原纤维，并且对于应力诱导的TDP-43液滴的分解是必需的。HSPB 1的减少促进胞质TDP-43的去混合和错误定位。在ALS患者脊髓运动神经元内鉴定出HSPB 1缺失，所述脊髓运动神经元含有聚集的TDP-43。这些发现确定HSPB 1是胞质TDP-43相分离和聚集的调节剂。
While acetylated, RNA binding deficient TDP-43 reversibly phase separates within nuclei into complex droplets (anisosomes) comprised of TDP-43-containing liquid outer shells and liquid centers of HSP70 family chaperones, cytoplasmic aggregates of TDP-43 are hallmarks of multiple neurodegenerative diseases, including ALS. Here we show that transient oxidative stress, proteasome inhibition, or inhibition of HSP70’s ATP-dependent chaperone activity provokes reversible cytoplasmic TDP-43 de-mixing and transition from liquid to gel/solid, independent of RNA binding or stress granules. Isotope labeling mass spectrometry is used to identify that phase separated cytoplasmic TDP-43 is bound by the small heat shock protein HSPB1. Binding is direct, mediated through TDP-43’s RNA binding and low complexity domains. HSPB1 partitions into TDP-43 droplets, inhibits TDP-43 assembly into fibrils, and is essential for disassembly of stress-induced TDP-43 droplets. Decrease of HSPB1 promotes cytoplasmic TDP-43 de-mixing and mislocalization. HSPB1 depletion is identified within ALS-patient spinal motor neurons containing aggregated TDP-43. These findings identify HSPB1 to be a regulator of cytoplasmic TDP-43 phase separation and aggregation.
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影响因子：
16.6
作者：
Cohen, Todd J.;Hwang, Andrew W.;Restrepo, Clark R.;Yuan, Chao-Xing;Trojanowski, John Q.;Lee, Virginia M. Y.
通讯作者：
Lee, Virginia M. Y.
DOI：
10.1074/jbc.m109.082644
发表时间：
2010-04-23
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Almeida-Souza L;Goethals S;de Winter V;Dierick I;Gallardo R;Van Durme J;Irobi J;Gettemans J;Rousseau F;Schymkowitz J;Timmerman V;Janssens S
通讯作者：
Janssens S
DOI：
10.1126/science.aaa3650
发表时间：
2015-03-27
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Cirulli ET;Lasseigne BN;Petrovski S;Sapp PC;Dion PA;Leblond CS;Couthouis J;Lu YF;Wang Q;Krueger BJ;Ren Z;Keebler J;Han Y;Levy SE;Boone BE;Wimbish JR;Waite LL;Jones AL;Carulli JP;Day-Williams AG;Staropoli JF;Xin WW;Chesi A;Raphael AR;McKenna-Yasek D;Cady J;Vianney de Jong JM;Kenna KP;Smith BN;Topp S;Miller J;Gkazi A;FALS Sequencing Consortium;Al-Chalabi A;van den Berg LH;Veldink J;Silani V;Ticozzi N;Shaw CE;Baloh RH;Appel S;Simpson E;Lagier-Tourenne C;Pulst SM;Gibson S;Trojanowski JQ;Elman L;McCluskey L;Grossman M;Shneider NA;Chung WK;Ravits JM;Glass JD;Sims KB;Van Deerlin VM;Maniatis T;Hayes SD;Ordureau A;Swarup S;Landers J;Baas F;Allen AS;Bedlack RS;Harper JW;Gitler AD;Rouleau GA;Brown R;Harms MB;Cooper GM;Harris T;Myers RM;Goldstein DB
通讯作者：
Goldstein DB
影响因子：
4.8
作者：
Babinchak, W. Michael;Haider, Raza;Surewicz, Witold K.
通讯作者：
Surewicz, Witold K.
影响因子：
16.8
作者：
Cao, Qin;Boyer, David R.;Eisenberg, David S.
通讯作者：
Eisenberg, David S.